Obesity is associated with adipose dysfunction, which contributes to insulin
resistance, diabetes, and heart disease.
It has been proposed that adipose dysfunction is caused by an inappropriate
response to hypoxia that results in increased ECM expression and reduced
angiogenesis.Our data indicate that
adipocyte-macrophage cross talk results in increased expression of
thrombospondin-1 (TSP-1), a multifunctional protein that promotes fibrosis by
activating TGF-beta signaling.TGF-beta
has multiple effects on adipose in addition to inducing fibrosis including
inhibiting adipogenesis and complicated effects on angiogenesis. Recently, a
whole-body knockout of SMAD3 to block TGF-beta signaling resulted in mice with
improved metabolic function and browning of their white adipose; this was due in
part to reversing the inhibition of TGF-beta on the expression of PGC-1 alpha.Our overall hypothesis is that increased TSP-1 expression and TGF-beta
signaling in white adipose with obesity cause increased fibrosis, reduced
capillary density, reduced PGC-1 alpha and reduced UCP-1 expression hence less
“browning”, and impaired WAT function.
Thus, inhibiting the TGF-beta pathway in humans may improve adipose function and
reverse the effects of obesity on insulin resistance.The first aim will characterize the white adipose ECM and capillary
density of TSP-1 knockout mice and their littermate controls challenged with a
high fat diet.The second aim will
knockout TGF-beta in adipose using cre/lox technology to elucidate the role of
TGF-beta signaling on adipose function is response to high fat feeding.The third aim will determine whether the dramatic reduction in adipocyte
PGC-1 alpha by macrophage coculture is TGF-beta dependent.The fourth aim will determine whether toll-like receptor (TLR) signaling
is involved in the adipocyte-macrophage crosstalk that induces TSP-1 and TGF-beta
signaling in macrophages.Thus, the two
mouse models will indicate the contribution of TSP-1 and TGF- beta to adipose
dysfunction with obesity.The coculture
studies will begin to define the mechanisms by which adipocytes and macrophages
communicate with each other to induce TSP-1 expression by both cells types and
to decrease PGC-1 alpha expression in adipocytes.